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CTAD 2022 | Meta-analysis of the latest anti-amyloid immunotherapies: benefit vs risk
Nicolas Villain, MD, PhD, AP-HP Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France, discusses results from a meta-analysis of the latest investigations into anti-amyloid immunotherapies to treat early Alzheimer’s disease (AD). The meta-analysis focused on the efficacy and safety of selected drugs responsible for a high clearance of amyloid, as measured by amyloid-PET. The analysis was performed on data from the high-dose groups of the lecanemab (NCT01767311) and donanemab (NCT03367403) Phase II clinical trials and the two aducanumab Phase III clinical trials (NCT02477800 and NCT02484547). Across the trials, the anti-amyloid therapies demonstrated a significant global effect on the progression of CDR-SB and ADAS-Cog, but not MMSE, after 18 months, compared to placebo. However, this effect remains below the established minimal clinically relevant outcome threshold. The safety of the drugs was measured using the occurrence of amyloid-related imaging abnormalities (ARIA), specifically ARIA that led to the hospitalization or death of a patient. Across the trials, 0.8% of patients suffered from serious ARIA. Given the relatively small clinical effect and the occurrence of serious ARIA, Dr Villain highlights the low benefit/risk ratio of this class of drugs and suggests identifying better responders or combination therapies to improve their clinical relevance. This interview took place at the Clinical Trials on Alzheimer’s Disease Congress 2022 in San Francisco.
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Transcript (edited for clarity)
What we actually tried to do is to put things into perspective from sometimes positive results, sometimes negative results from recently performed Phase III or Phase II anti-amyloid immunotherapies. So we try to put those all together and see what this tells us about these drugs, about their efficacy, about their side effects. So we made a choice, which was only to select the drugs that were responsible for the high clearance of amyloid as measured with amyloid-PET, because we considered that it was a recent game changer in anti-amyloid immunotherapy since the PRIME study from aducanumab...
What we actually tried to do is to put things into perspective from sometimes positive results, sometimes negative results from recently performed Phase III or Phase II anti-amyloid immunotherapies. So we try to put those all together and see what this tells us about these drugs, about their efficacy, about their side effects. So we made a choice, which was only to select the drugs that were responsible for the high clearance of amyloid as measured with amyloid-PET, because we considered that it was a recent game changer in anti-amyloid immunotherapy since the PRIME study from aducanumab. So we decided only to gather data from these drugs, which means that we gathered data from donanemab Phase II, aducanumab Phase III, gantenerumab Phase III, GRADUATE I and II, and of course lecanemab Phase II and III.
So we gathered all of this data together, which was actually reasonable since all these trials besides the gantenerumabs were performed on 18 months. So we had a common outcome at 18 months, and the primary outcome was always measured with CDR-SB, so we had a similar primary outcome for all of these trials and the inclusion criteria were quite similar, which means early stages of Alzheimer’s disease with MMSE of 20, it could depend from one study to another, sometimes 22. But anyway, it was early stage AD with at least an amyloid biomarker.
So all of these trials were actually very similar. So that’s why we decided to do a meta-analysis on them and what we could see is that it was actually very consistent across this trial, despite the fact that some were positive, some were negative. The mean effect on the CDR-SB was very consistent from one trial to another, moving from 0.2 to 0.45. And as a mean we had a 0.3 effect on the CDR-SB, which was significant in our meta-analysis. But that was not the point to show a statistical effect on this meta-analysis.
So we had a very consistent effect on cognition with these drugs and on the other hand, we of course have side effects, ARIA, and what we tried to see was if we could measure the frequency of serious ARIA because in our opinion, ARIA is of course a problem, but it can be most of the time easily handled just with dose suspension and patients recover and that’s fine, we can keep going. ARIA is of course a problem, but usually it’s not a problem for the patient as long as we deal with it correctly. What we were more concerned about were the serious ARIA, ARIA that led to a hospitalization or death of a patient. So we try to gather this results across the trial and across all this trial we could actually measure that it happens in about 0.8% of patient. So it was quite high to our opinion.
About 1%, 0.8% of patient on any of these drugs will at some point go to the hospital because of the side effects. And if we give them to millions of people, that’s of course a concern because tens of thousands of people will end up with this kind of condition. So that’s why we wanted to do this meta-analysis, to see if it was consistent across trials and the cognitive effect, and if we could better quantify the risk of the serious ARIA. And this, in our opinion, helps the physician to measure the risk benefit ratio of this drug, which is statistically significant again on cognition but not very meaningful, 0.3, 0.4, 0.2 CDR-SB point is below the minimal clinical important differences. And besides, we have this 0.8% risk of serious ARIA.
So we really need to balance that when we make this kind of decision. Of course, it’s very good news for the field, for science that we with anti-amyloid immunotherapy, can have a treatment for Alzheimer’s disease and can stop its progression. And the scientist in me is of course very happy, but the physician also says, “”Okay, it’s very good news on the breakthrough thing for the field, but it’s not a miracle drug so far and we should remain careful and find individuals who could be better responders or find a new combination therapy or develop new drugs with better safety profiles.”” Anyway, it may be a breakthrough thing, but we need to do better for a good drug for our patients.
Independent of this work, NV received research support from Fondation Bettencourt-Schueller, Fondation Servier, Union Nationale pour les Intérêts de la Médecine (UNIM), Fondation Claude Pompidou, Fondation Alzheimer and Fondation pour la Recherche sur l’Alzheimer; travel grant from the Movement Disorders Society, Merz-Pharma, UCB Pharma, and GE Healthcare SAS; is an unpaid local principal investigator or sub-investigator in NCT04241068 and NCT05310071 (aducanumab, Biogen), NCT04437511 (donanemab, Eli-Lilly), NCT05463731 (remternetug, Eli-Lilly), NCT04592341 (gantenerumab, Roche), NCT03887455 (lecanemab, Eisai), NCT03352557 (gosuranemab, Biogen), NCT03828747 and NCT03289143 (semorinemab, Roche), NCT04619420 (JNJ-63733657, Janssen – Johnson & Johnson), NCT04374136 (AL001, Alector), NCT04592874 (AL002, Alector), NCT04867616 (bepranemab, UCB Pharma), NCT04777396 and NCT04777409 (semaglutide, Novo Nordisk), is an unpaid national coordinator for NCT05564169 (masitinib, ABScience); and has given unpaid lectures in symposia organized by Eisai and the Servier Foundation.